The major goals of these studies are to elucidate the individual roles of COX-1 and COX-2 in normal physiology and in various pathological states. Specifically, effort within the laboratory has focused on using COX-2 deficient mouse ES cells and COX specific inhibitors to study the roles of COX-2 in endothelial cell development and aneurysm formation. Endothelial cell ifferentiation was measured immunohistochemically by the appearance of CD-31 staining cord like structures of cells and the appearance of VEGF receptors and COX-2 on Western analysis. Our studies indicated that the deficiency of COX-2 inhibited mouse ES cell differentiation into endothelial-like cells in vitro. However, studies with COX-2 selective inhibitors have indicated that the COX-2 inhibitors blocked endothelial-like cell development even in COX-2-/- ES cells, suggesting that a COX-2 independent mechanism was responsible. In addition, a mouse model to study the contributions of COX-2 to aneurysm formation is being developed and initial studies indicate that COX-2 deficiency attenuates inflammatory responses in the mouse heart and abdominal vasculature. Also, collaborative studies have demonstrated that COX-2 deficiency increased inflammatory responses in the mouse brain.